The rediscovery of estetrol and its implications for estrogen treatment.

Estetrol (E4) was rediscovered as the fourth natural estrogen more than 100 years after the discovery of estrone (E1), estradiol (E2), and estriol (E3).

• E1, E2, and E3 were discovered prior to the recognition of E4 as a distinct natural estrogen.
• The paper describes E4's rediscovery as a significant event in the history of estrogen science.
• E4 is distinguished from the other three natural estrogens by its unique pharmacological properties.

Contrary to the other three natural estrogens, E4 has a high oral bioavailability.

• High oral bioavailability is identified as a key distinguishing characteristic of E4 compared to E1, E2, and E3.
• This property was revealed through preclinical and clinical research and development of E4.
• High oral bioavailability makes E4 particularly suitable for oral administration.

Oral E4 has limited effect on hemostasis and other liver functions compared to other estrogens.

• The limited hepatic effect is described as a finding from preclinical and clinical research and development.
• Due to these limited effects on hemostasis and liver functions, E4 is expected to be a safer estrogen.
• These properties distinguish E4 from other orally administered estrogens, which typically have more pronounced liver effects.

E4 combined with drospirenone has been registered worldwide as an oral contraceptive since 2022.

• Registration occurred worldwide starting in 2022.
• The contraceptive formulation combines E4 with the progestogen drospirenone.
• This represents the first approved clinical application of E4.

E4 for menopausal hormone therapy is expected to become available in 2026.

• Clinical development for menopausal hormone therapy is described as being in progress.
• Availability is projected for 2026.
• This application leverages E4's expected safety advantages over existing estrogen therapies.

Clinical development of E4 for treatment of advanced breast cancer and advanced prostate cancer is ongoing.

• Both advanced breast cancer and advanced prostate cancer are identified as therapeutic targets under clinical development.
• The use of an estrogen for these cancer indications reflects E4's distinct pharmacological profile.
• This represents an extension of E4's clinical applications beyond contraception and menopausal hormone therapy.

E4 has been proposed as a component of an oral male contraceptive.

• The proposal extends E4's potential use to male contraception.
• This application is described alongside other ongoing and anticipated clinical uses.
• The authors note that E4 recognition is expected to change the scene of estrogen treatment in both women and men significantly.